TY - JOUR
T1 - Impact of perturbed pancreatic β-cell cholesterol homeostasis on adipose tissue and skeletal muscle metabolism
AU - Cochran, Blake J.
AU - Hou, Liming
AU - Manavalan, Anil Paul Chirackal
AU - Moore, Benjamin M.
AU - Tabet, Fatiha
AU - Sultana, Afroza
AU - Torres, Luisa Cuesta
AU - Tang, Shudi
AU - Shrestha, Sudichhya
AU - Senanayake, Praween
AU - Patel, Mili
AU - Ryder, William J.
AU - Bongers, Andre
AU - Maraninchi, Marie
AU - Wasinger, Valerie C.
AU - Westerterp, Marit
AU - Tall, Alan R.
AU - Barter, Philip J.
AU - Rye, Kerry Anne
N1 - An erratum exists for this article in Diabetes (2017) Vol 66 (2) and can be found at doi: 10.2337/db17-er02b
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Elevated pancreatic βcell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: Adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.
AB - Elevated pancreatic βcell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: Adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=85000443553&partnerID=8YFLogxK
UR - https://doi.org/10.2337/db17-er02b
U2 - 10.2337/db16-0668
DO - 10.2337/db16-0668
M3 - Article
C2 - 27702832
AN - SCOPUS:85000443553
VL - 65
SP - 3610
EP - 3620
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -